Regio- and Diastereoselective Synthesis of Dihydropyridopyrimidines

May 24, 2017 - Regio- and Diastereoselective Synthesis of Dihydropyridopyrimidines via Cascade Reactions of 2-Aminopyridines with Morita–Baylis–Hi...
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Regio- and Diastereoselective Synthesis of Dihydropyridopyrimidines via Cascade Reactions of 2‑Aminopyridines with Morita−Baylis−Hillman Bromides of Nitroalkenes Lakshminarayana Satham and Irishi N. N. Namboothiri* Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India S Supporting Information *

ABSTRACT: The Morita−Baylis−Hillman (MBH) bromides of nitroalkenes have been employed as bielectrophiles for the first time. The 1,3-bielectrophilic reactivity of the MBH bromides has been demonstrated in the synthesis of 3,4-dihydro-2Hpyrido[1,2-a]pyrimidines. The reaction of MBH bromides with 2-aminopyridines takes place in the absence of any reagent in a cascade SN2′-6-endo-trig fashion and is completely regioselective and highly stereoselective. The products, in their hydrobromide salt form, could be conveniently isolated and purified by crystallization. The high stereoselectivity has been rationalized in terms of the greater stability of the transition state in which the Ar and NO2 groups are anti to each other.

N

the synthesis of complex molecules including natural products.22−24 Its vinylogous version, the Rauhut−Currier (RC) reaction, though limited in substrate scope, also made considerable impact due to its simplicity and applicability in synthesis.25 The MBH and RC reactions of nitroalkenes have delivered a diverse array of molecules in recent years for applications as synthetic intermediates and biological agents.26 In particular, the electrophilic reactivity, including the 1,2- and 1,3-bielectrophilic reactivities, of MBH acetates 226−28 and 526,29 has been extensively exploited for the synthesis of various heterocycles and even carbocycles. In 2012, we reported the synthesis of imidazopyridines 3 from MBH acetates 2 and 2aminopyridines 1 through an SN2′-5-exo-trig cyclization by exploiting the 1,2-bielectrophilic nature of acetates 2 (Scheme 1a).28 The imidazopyridines 3 could be easily transformed to anxiolytic drug Alpidem 4a and hypnotic drug Zolpidem 4b in a minimum number of steps. However, our initial attempts to synthesize pyridopyrimidines, the 6−6-fused systems, 7 or 8 from MBH acetates 5 and aminopyridine 1a did not yield positive results (Scheme 1b). At this juncture, we felt that a better leaving group (LG = Br) would enable us to successfully carry out the desired SN2′-6-endo-trig-cyclization and construct pyridopyrimidine 7. In the case of such primary allylic bromides 6,30 an alternative SN2−6-endo-trig cyclization to afford the regioisomeric pyridopyrimidine 8 also appeared possible. To our knowledge, such 1,3-bielectrophilic reactivity of nitroallylic bromide 6 is not documented in the literature. Therefore, we

itrogenous heterocycles play a pivotal role in the bioactivity of natural products and pharmaceuticals.1 Heterocyclic ammonium salts,2 in particular, exhibit CFTR activation,3 DNA-intercalating antiproliferative activity4 as well as antimalarial and antileishmanial activities,5 to name a few. Saturated and partially saturated pyrido[1,2-a]pyrimidines belong to the broad class of bioactive bicyclic 6−6 fused systems bearing one nitrogen at the ring junction and another nitrogen elsewhere in the ring.6 Numerous small bioactive molecules have evolved from the pyrido[1,2-a]pyrimidine skeleton which now emerged as a privileged scaffold in medicinal chemistry.7 Various pyrido[1,2a]pyrimidines employed in human therapy include neuroleptic risperidone,8 tranquilizer pirenperone,9 antiallergic ramastine,10 antidepressant lusaperidone,11 and non-narcotic analgesic rimazolium (Figure 1).12 Pyrido[1,2-a]pyrimidines are also potent inhibitors of nitric oxide synthases (NOS).13 The diverse bioactivities displayed by pyridopyrimidines motivated synthetic organic and medicinal chemists to develop novel and convenient methods for their synthesis.14 These include reactions involving aminopyridines in formal azaDiels−Alder reaction,15 intramolecular cyclization,16 cyclization with 1,3-bielectrophiles,13,17 multicomponent reactions,18 cyclocondensation,19 and metal mediated sequence.20 Synthetic approaches not involving aminopyridines are also known in the literature.21 However, the synthesis of pyridopyrimidines from readily available starting materials in a regio- and stereoselective manner is still an attractive objective. From another perspective, the Morita−Baylis−Hillman (MBH) reaction is an elegant methodology for the synthesis of multifunctional molecules that serve as valuable substrates in © 2017 American Chemical Society

Received: April 20, 2017 Published: May 24, 2017 6482

DOI: 10.1021/acs.joc.7b00947 J. Org. Chem. 2017, 82, 6482−6488

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The Journal of Organic Chemistry

Figure 1. Biologically active pyridopyrimidines.

(14 h, 75:25 vs 24 h, 69:31). A marginal drop in the reaction rate, product yield, and diastereoselectivity (24−36 h, 84−85% yield, 71:79 to 75:25) was observed in the case of CH3CN and toluene. Overall, THF turned out to be the best solvent for our reaction. The reactions performed in THF at lower temperatures, 0 °C and −50 °C, required a longer time for completion with a marginal drop in the yield and diastereoselectivity (30− 36 h, 90−93% yield, 66:34 to 72:28). Attempts to accelerate the reaction by heating (50 °C) or by using a catalyst such as DABCO led to decomposition of the product. The above reaction conditions, viz THF, room temperature, were employed to investigate the scope of MBH bromides 6 and aminopyridines 1 (Tables 1 and 2). As for the scope of

Scheme 1. Reactivity of MBH Adducts of Nitroalkenes with 2-Aminopyridines

Table 1. Scope of MBH Bromides 6

report herein the synthesis of pyrido[1,2-a]pyrimidines 7 from MBH bromide 6 and 2-aminopyridine 1 via a cascade SN2′-6endo-trig cyclization, the second step of which is also an intramolecular aza-Michael addition. The reaction conditions were optimized using MBH bromide 6a and aminopyridine 1a as the model substrates (Scheme 2).

entry

6

Ar

time (h)

7

% yielda

drb

1 2 3 4 5 6 7

6a 6b 6c 6d 6e 6f 6g

4-MeOC6H4 3,4-(MeO)2C6H3 3,4-(OCH2O)2C6H3 4-MeC6H4 1-Naphthyl 4-ClC6H4 3-BrC6H4

14 14 14 20 18 24 27

7a 7b 7c 7d 7e 7f 7g

98 98 97 92 91 80 94

75:25 93:07 >95:05 75:25 90:10 64:36 94:06

Scheme 2. Optimized Reaction Conditions

a

After isolation by crystallization. bDetermined by the 1H NMR of the crude product.

MBH bromides 6, β-aryl derivatives possessing diverse electron demands, such as those bearing strongly electron donating groups 6a−c, weakly electron donating group 6d, electroneutral but sterically demanding 6e, and weakly electron withdrawing 6f−g were evaluated for their reactivity with aminopyridine 1a. The product yields and reaction times were very impressive for those bearing electron rich aryl groups 7a−c (97−98%, 14 h, entries 1−3). Unlike in the case of 7a (dr 75:25, entry 1), the diastereoselectivity of 7b−c were excellent (93:7 to >95:5, entries 2−3). Marginally longer reaction times (18−20 h) were observed in the case of 6d−e giving the corresponding products 7d−e in marginally lower yields (91−92%), but the

At the outset, these two reactants were stirred at room temperature in a polar protic solvent such as MeOH in the absence of any base. To our delight, the pyridopyrimidinium bromide 7a began precipitating out as a yellow solid in 15 min, and the reaction was complete in 14 h. More importantly, a single regioisomer 7a was formed, though with moderate diastereoselectivity (67:33) in nearly quantitative yield. At this juncture, solvents representing other categories such as halogenated (CH2Cl2), polar aprotic (THF, CH3CN), and nonpolar (toluene) were screened. While the yields remained nearly quantitative in CH2Cl2 and THF (98%), THF was superior both in terms of reaction time and diastereoselectivity 6483

DOI: 10.1021/acs.joc.7b00947 J. Org. Chem. 2017, 82, 6482−6488

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The Journal of Organic Chemistry

followed by elimination of bromide (overall SN2′ reaction) generating intermediate I. A second aza-Michael addition, this time in an intramolecular 6-endo-trig fashion, leads to the formation of product 7. The intramolecular aza-Michael addition of intermediate I to form products 7 takes place through two diastereomeric transition states II-gauche or II-anti. Since there is a possibility of intramolecular H-bonding between N−H and NO2 in both transitions states, the key factor that controls the stereoselectivity appeared to be the relative stabilities of II-gauche and II-anti, i.e., in terms of the orientation of the Ar group with respect to the nitro group. It is evident from the X-ray crystal structure of 7b that the six-membered ring has half-chair conformation and the dihedral angle between Ar and NO2 is ∼165°. This suggests that the more stable transition state is IIanti, which leads to the trans isomer as the major product. In summary, we have developed a regio- and diastereoselective synthesis of dihydropyrido[1,2-a]pyrimidines involving a cascade SN2′-intramolecular aza-Michael addition involving nitroallylic bromide, derived from a Morita−Baylis−Hillman adduct of nitroalkene, as the 1,3-bielectrophile and aminopyridine as the 1,3-binucleophile. The reaction proceeds at room temperature in THF in the absence of any base and has broad substrate compatibility. The regio- and stereochemistry of the products was unambiguously established by single crystal X-ray analysis of a representative compound and explained by a suitable TS model. Formation of the trans-diastereomer as the major product was attributed to greater stability of the corresponding transition state in which the Ar and NO2 groups are anti to each other.

Table 2. Scope of 2-Aminopyridines 1

entry

1

R

time (h)

7

% yielda

drb

1 2 3 4 5

1b 1c 1d 1e 1f

4-Cl 5-Cl 5-Br 5-NO2 5-Br, 4-Me

48 48 24 72 54

7h 7i 7j 7k 7l

97 92 90 68 78

88:12 74:26 82:18 86:14 80:20

a

After isolation by crystallization. bDetermined by 1H NMR of the crude product.

diastereoselectivities were superior in the case of 7e (90:10, entries 4−5). Although the reaction times were comparable for 6f and 6g (24−27 h), the corresponding products 7f and 7g were formed with a considerable difference in yield and diastereoselectivities (entries 6−7). Subsequently, aminopyridines 1 bearing substituents at 4 and/or 5 positions were treated with a representative MBH bromide 6a under the optimized conditions (Table 2). Although the reaction times were much longer for these substituted aminopyridines 1b−f compared to those for unsubstituted 1a (Table 1), the yields remained excellent (90−97%, entries 1−3), except for the ones with strongly deactivating substituent and multiple substituents 1e and 1f, respectively (entries 4−5). The diastereoselectivity remained in the range of 74:26 to 88:12. Other 2-aminoazaheterocycles such as 2-aminopyrimidine 9a and 2-aminopyrazine 9b which did not react with secondary MBH acetate 2 during our previous work28 also reacted with a representative MBH bromide 6a and afforded fused heterocycles 10a and 10b, respectively, in excellent yield (95−98%) and moderate to good diastereoselectivity (70:30 to 86:14, Scheme 3).

■

GENERAL EXPERIMENTAL DETAILS

The melting points recorded are uncorrected. NMR spectra (1H, 1H decoupled 13C, and 1H−1H COSY) were recorded with TMS as the internal standard. The coupling constants (J values) are given in Hz. High resolution mass spectra were recorded under ESI Q-TOF conditions. X-ray data were collected on a diffractometer equipped with graphite monochromated Mo Kα radiation. The structure was solved by direct methods Shelxs97 and refined by full-matrix leastsquares against F2 using Shelxl97 software. General Procedure for the Synthesis of Dihydro-pyrido, Pyrimidino, and Pyrazinopyrimidines 7 and 10. To a stirred solution of MBH bromide 6 (0.3 mmol, 1.0 equiv) in THF (2 mL) was added 2-amino aza-heterocycle 1 or 9 (0.3 mmol, 1.0 equiv). The reaction mixture was stirred at rt, and the progress of the reaction was monitored by TLC (disappearance of starting materials and appearance of a fluorescent product spot on the baseline). After completion of the reaction, the solvent was evaporated in vacuo, the crude residue was taken up in CHCl3/diethyl ether (1:1, 10 mL) and was sonicated several times. The suspension was filtered to afford pure product 7 or 10 as a solid inseparable mixture of diastereomers. 2-(4-Methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7a). White solid; yield 110 mg, 98% (dr 75:25, inseparable); mp 232−234 °C; IR (KBr, cm−1) 3432 (br w), 3157 (w), 3089 (w), 3008 (m), 2936 (s), 2895 (vs), 2839 (s), 1657 (vs), 1597 (s), 1575 (s), 1551 (s), 1513 (s), 1300 (m), 1250 (s), 1179 (m), 1160 (m), 1033 (m), 779 (s); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 3.77 (s, 3H), 4.51 (d, J = 14.4 Hz, 1H), 5.07 (d, J = 14.4 Hz, 1H), 5.51−5.55 (unresolved, 1H), 5.78−5.82 (unresolved, 1H), 7.00−7.04 (unresolved, 3H), 7.29−7.33 (unresolved, 1H), 7.41 (d, J = 7.3 Hz, 2H), 7.95−7.99 (unresolved, 1H), 8.16−8.20 (unresolved, 1H), 10.34 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.99 (d, J = 14.8 Hz, 1H), 5.15 (d, J = 14.8 Hz, 1H), 10.06 (br s, 1H); 13C{1H} NMR (DMSOd6, 125 MHz, major) δ 47.7, 53.3, 55.3, 78.7, 113.4, 114.3, 114.4, 128.0, 128.3, 139.4, 142.6, 150.6, 159.6; 13C{1H} NMR (DMSO-d6,

Scheme 3

Interestingly, all of the products described above were isolated in their hydrobromide salt form by crystallization from a CHCl3/diethyl ether (1:1) solvent system after sonication. The relative stereochemistry of Ar and NO2 groups in the major isomer of compounds 7 and 10 was found to be trans by single crystal X-ray analysis of a representative compound 7b (see the Supporting Information). Having established the structure and stereochemistry of compounds 7 and 10 by spectroscopic analysis and X-ray crystallography, a plausible mechanism for their formation is proposed taking pyridopyrimidines 7 as the representative products (Scheme 4). It involves the intermolecular azaMichael addition of aminopyridine 1 through the primary amino group as the nucleophilic center to MBH bromide 6 6484

DOI: 10.1021/acs.joc.7b00947 J. Org. Chem. 2017, 82, 6482−6488

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The Journal of Organic Chemistry Scheme 4. Plausible Mechanism

125 MHz, minor) δ 50.2, 52.6, 55.2, 78.1, 113.5, 114.2, 114.6, 125.8, 128.9, 139.0, 141.9, 151.5, 159.8; MS (ES+, Ar) m/z HRMS calcd for C15H16N3O3 ([M-Br]+) 286.1186; found, 286.1187. 2-(3,4-Dimethoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7b). White solid; yield 117 mg, 98% (dr 93:07, inseparable); mp 233−235 °C; IR (KBr, cm−1) 3438 (br m), 3094 (m), 3057 (m), 3008 (s), 2940 (vs), 2905 (vs), 2835 (s), 1658 (vs), 1599 (vs), 1574 (vs), 1556 (s), 1518 (vs), 1257 (vs), 1241 (s), 1162 (s), 1146 (s), 1125 (m), 1022 (s), 858 (m), 764 (s); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 3.76 (s, 3H), 3.79 (s, 3H), 4.48 (d, J = 13.7 Hz, 1H), 5.07 (d, J = 13.7 Hz, 1H), 5.49−5.53 (unresolved, 1H), 5.86−5.90 (unresolved, 1H), 6.92 (unresolved d, 1H), 7.01 (unresolved d, 1H), 7.02 (unresolved t, 1H), 7.16 (s, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.97 (unresolved t, 1H), 8.16 (unresolved d, 1H), 10.51 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.96 (d, J = 13.7 Hz, 1H), 5.16 (d, J = 13.7 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H), 10.19 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 48.3, 54.0, 56.1, 56.2, 79.2, 110.9, 112.2, 113.8, 114.9, 119.5, 129.8, 139.8, 143.0, 149.5, 149.7, 151.1; MS (ES+, Ar) m/z HRMS calcd for C16H18N3O4 ([M-Br]+) 316.1292; found, 316.1293. Selected X-ray data: C16 H18 BrN3 O4, M 396.24, monoclinic, space group P21/c, a = 10.7705(7) Å, b = 10.1713(6) Å, c = 15.4078(9) Å, α = 90°, β = 97.569(6)°, γ = 90°, V = 1673.21(17) Å3, Dc = 1.573 mg/m3, Z = 4, F(000) = 808, λ = 0.71073 Å, μ = 2.482 mm−1, total/unique reflections = 7073/2944 [R(int) = 0.0430], T = 293(2) K, θ range = 2.41 to 25.00°. final R[I > 2σ(I)]: R1 = 0.0497, wR2 = 0.1412. R (all data): R1 = 0.0606, wR2 = 0.1499. 2-(Benzo[d][1,3]dioxol-5-yl)-3-nitro-3,4-dihydro-2H-pyrido[1,2a]pyrimidin-1-ium Bromide (7c). White solid; yield 112 mg, 97% (dr >95:05, inseparable); mp 201−203 °C; IR (KBr, cm−1) 3435 (br m), 2930 (m), 2899 (m), 1655 (s), 1591 (s), 1574 (s), 1556 (s), 1506 (m), 1491 (m), 1258 (s), 1038 (s); 1H NMR (DMSO-d6, 500 MHz, major) δ 4.51 (d, J = 14.6 Hz, 1H), 5.06 (d, J = 14.6 Hz, 1H), 5.48− 5.52 (unresolved, 1H), 5.75−5.79 (unresolved, 1H), 6.07 (s, 2H), 6.93, 6.98 (ABq, J = 7.6 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.96 (t, J = 7.2 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 10.39 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 47.7, 53.4, 78.6, 101.5, 107.3, 108.4, 113.3, 114.4, 120.7, 130.9, 139.3, 142.5, 147.7, 147.8, 150.5; MS (ES+, Ar) m/z HRMS calcd for C15H14N3O4 ([M-Br]+) 300.0979; found, 300.0978. 3-Nitro-2-(p-tolyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7d). White solid; yield 96 mg, 92% (dr 75:25, inseparable); mp 214−216 °C; IR (KBr, cm−1) 3465 (br m), 3082 (m), 3016 (m), 2917 (s), 2896 (s), 2851 (m), 1653 (s), 1595 (s), 1568 (s), 1550 (s), 1157 (m), 862 (m), 781 (s); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 2.32 (s, 3H), 4.46 (dd, J = 15.4, 2.5 Hz, 1H), 5.06 (dd, J = 15.4, 2.5 Hz, 1H), 5.54−5.58 (unresolved, 1H), 5.77−5.80 (m, 1H), 7.03 (t, J = 6.5 Hz, 1H), 7.24 (d, J = 6.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.97 (t, J = 6.5 Hz, 1H), 8.13 (d, J = 6.5 Hz, 1H), 10.19 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.95 (dd, J = 14.9, 3.6 Hz, 1H), 5.12 (d, J = 14.9 Hz, 1H), 8.10 (d, J = 6.6 Hz, 1H), 10.00 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 20.7, 47.7, 53.6, 78.7, 113.5,

114.4, 126.8, 129.7, 134.2, 138.5, 139.5, 142.8, 150.6; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 20.8, 50.3, 52.9, 78.1, 113.6, 114.7, 126.7, 129.5, 131.1, 138.8, 139.1, 142.1, 151.5; MS (ES+, Ar) m/z HRMS calcd for C15H16N3O2 ([M-Br]+) 270.1237; found, 270.1235. 2-(Naphthalen-1-yl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7e). White solid; yield 107 mg, 91% (dr 90:10, inseparable); mp 240−242 °C; IR (KBr, cm−1) 3459 (br s), 2923 (m), 2885 (s), 2849 (s), 2825 (s), 1654 (s), 1597 (s), 1575 (s), 1551 (s), 1166 (m), 803 (m), 778 (m), 760 (m); 1H NMR (DMSOd6, 500 MHz, major + minor) δ 4.40 (d, J = 14.6 Hz, 1H), 5.09 (d, J = 14.6 Hz, 1H), 5.93−5.97 (unresolved, 1H), 6.46−6.50 (unresolved, 1H), 7.05−7.15 (unresolved, 1H), 7.35−7.45 (unresolved, 1H), 7.52− 7.62 (m, 2H), 7.65−7.75 (unresolved, 1H), 7.75−7.83 (unresolved, 1H), 8.02−8.15 (m, 3H), 8.22−8.34 (m, 2H), 10.29 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 5.28−5.30 (unresolved, 1H), 10.13 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 46.9, 51.5, 77.4, 113.6, 114.4, 121.9, 125.3, 125.5, 126.5, 127.6, 128.8, 129.3, 129.7, 132.5, 133.5, 139.4, 142.7, 150.7; MS (ES+, Ar) m/z HRMS calcd for C18H17N3O2 ([MBr]+) 307.1315; found, 307.1312. 2-(4-Chlorophenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7f). White solid; yield 88 mg, 80% (dr 64:36, inseparable); mp 231−233 °C; IR (KBr, cm−1) 3451 (br s), 2890 (m), 1654 (vs), 1596 (s), 1569 (s), 1549 (m), 1492 (w), 1160 (w), 861 (w), 776 (m); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 4.48 (d, J = 14.7 Hz, 1H), 5.10 (d, J = 14.7 Hz, 1H), 5.64− 5.70 (unresolved, 1H), 5.84−5.88 (unresolved, 1H), 7.02−7.08 (unresolved, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.44−7.48 (unresolved, 1H), 7.51−7.58 (unresolved, 3H), 7.96−8.03 (unresolved, 1H), 8.15− 8.22 (unresolved, 1H), 10.30 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 5.03 (d, J = 14.8 Hz, 1H), 5.19 (d, J = 14.8 Hz, 1H), 5.87−5.91 (unresolved, 1H), 7.40 (d, J = 8.2 Hz, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 47.6, 52.9, 78.3, 113.5, 114.3, 128.9, 129.0, 133.6, 136.2, 139.4, 142.7, 150.6; 13 C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 50.2, 52.4, 78.0, 113.6, 114.6, 128.7, 128.8, 133.1, 133.8, 139.1, 142.1, 151.4; MS (ES+, Ar) m/z HRMS calcd for C14H13ClN3O2 ([M-Br]+) 290.0691; found, 290.0701. 2-(3-Bromophenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7g). White solid; yield 117 mg, 94% (dr 94:06, inseparable); mp 205−207 °C; IR (KBr, cm−1) 3445 (br s), 3094 (m), 3002 (m), 2975 (m), 2924 (m), 2896 (s), 2848 (s), 2774 (m), 1657 (s), 1597 (s), 1577 (s), 1556 (s), 1387 (m), 1320 (s), 1301 (m), 1165 (s), 798 (m), 761 (s); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 4.48 (dd, J = 14.3, 2.2 Hz, 1H), 5.09 (d, J = 14.3 Hz, 1H), 5.67 (unresolved, 1H), 5.88 (unresolved, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.41−7.44 (m, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.99 (t, J = 7.5 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 10.33 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.97 (d, J = 15.3 Hz, 1H), 5.18 (d, 15.3 Hz, 1H), 5.62 (unresolved, 1H), 10.12 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, tautomer) δ 3.55 (dd, J = 15.8, 3.3 Hz, 1H), 4.12 (d, J = 15.8 Hz, 1H), 5.92 (unresolved, 1H), 6.69 (s, 1H), 6485

DOI: 10.1021/acs.joc.7b00947 J. Org. Chem. 2017, 82, 6482−6488

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The Journal of Organic Chemistry

500 MHz, major + minor) δ 3.78 (s, 3H), 4.59 (d, J = 15.0 Hz, 1H), 5.28 (d, J = 15.0 Hz, 1H), 5.67−5.72 (unresolved, 1H), 5.77−5.81 (unresolved, 1H), 7.03 (d, J = 7.4 Hz, 2H), 7.36 (d, J = 9.5 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 8.58 (d, J = 9.5 Hz, 1H), 9.50 (s, 1H), 11.35 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 5.02 (d, J = 14.5 Hz, 1H), 5.62−5.66 (unresolved, 1H), 5.77−5.81 (unresolved, 1H), 7.31 (d, J = 7.7 Hz, 1H), 9.44 (s, 1H); 13 C{1H} NMR (DMSO-d6, 125 MHz, major) δ 48.5, 53.7, 55.4, 78.1, 114.4, 114.7, 128.0, 128.7, 135.3, 135.5, 140.4, 152.1, 159.8; MS (ES+) m/z HRMS calcd for C15H15N4O5 ([M-Br]+) 331.1037; found, 331.1038. 7-Bromo-2-(4-methoxyphenyl)-8-methyl-3-nitro-3,4-dihydro-2Hpyrido[1,2-a]pyrimidin-1-ium Bromide (7l). White solid; yield 108 mg, 78% (dr 80:20, inseparable); mp 177−179 °C; IR (KBr, cm−1) 3437 (br vs), 2960 (m), 2917 (m), 1656 (s), 1592 (s), 1582 (s), 1556 (s), 1513 (m), 1363 (m), 1254 (s), 1180 (m), 1024 (s), 803 (m); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 2.40 (s, 3H), 3.76 (s, 3H), 4.42 (d, J = 14.1 Hz, 1H), 5.07 (d, J = 14.1 Hz, 1H), 5.52−5.56 (unresolved, 1H), 5.77−5.81 (unresolved, 1H), 6.98−7.02 (unresolved, 2H), 7.27 (s, 1H), 7.38−7.42 (unresolved, 2H), 8.62 (s, 1H), 10.43 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.48−5.02 (unresolved, 1H), 7.31 (d, J = 8.8 Hz, 2H), 8.40 (s, 1H), 10.15 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 22.4, 47.1, 53.0, 55.3, 78.5, 109.1, 113.7, 114.4, 128.1, 128.3, 139.0, 149.3, 153.8, 159.6; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 22.4, 49.9, 52.6, 55.3, 77.9, 79.4, 114.0, 114.2, 125.7, 128.9, 138.7, 150.3, 153.1, 159.8; MS (ES+, Ar) m/z HRMS calcd for C16H17BrN3O3 ([M-Br]+) 378.0448; found, 378.0439. 2-(4-Methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-1-ium Bromide (10a). Yellow solid; yield 108 mg, 98% (dr 70:30, inseparable); mp 212−214 °C; IR (KBr, cm−1) 3590 (br w), 3422 (br m), 3265 (w), 3093 (s), 2922 (m), 1651 (vs), 1595 (vs), 1573 (vs), 1512 (s), 1310 (s), 1268 (vs), 1182 (s); 1H NMR (DMSOd6, 500 MHz, major + minor) δ 3.77 (s, 3H), 4.49 (dd, J = 15.3, 3.0 Hz, 1H), 5.12 (d, J = 15.3 Hz, 1H), 5.58−5.62 (unresolved m, 1H), 5.73−5.77 (unresolved m, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.23−7.26 (m, 1H), 7.46 (d, J = 8.6 Hz, 2H), 8.67−8.69 (m, 1H), 8.97−8.99 (m, 1H), 10.85 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 5.00 (dd, J = 15.3, 3.0 Hz, 1H), 5.19 (d, J = 15.3 Hz, 1H), 5.81−5.85 (unresolved, 1H), 10.85 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 48.1, 54.0, 55.4, 78.4, 111.1, 114.4, 128.1, 128.5, 149.5, 152.2, 159.7, 166.8; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 50.4, 53.6, 55.3, 77.9, 110.0, 114.2, 125.4, 128.9, 149.2, 153.1, 159.9, 166.1; MS (ES+, Ar) m/z HRMS calcd for C14H15N4O3 ([M-Br]+) 287.1139; found, 286.1136. 2-(4-Methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidin-1-ium Bromide (10b). Brown solid; yield 104 mg, 95% (dr 86:14, inseparable); mp 183−185 °C; IR (KBr, cm−1) 3435 (br m), 3064 (m), 2983 (s), 2927 (s), 2753 (vs), 1637 (s), 1608 (vs), 1558 (s), 1511 (m), 1373 (m), 1247 (s), 1178 (m), 1142 (m), 1032 (m), 859 (m), 838 (m); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 3.79 (s, 3H), 4.50 (d, J = 14.4 Hz, 1H), 5.09 (d, J = 14.4 Hz, 1H), 5.61−5.65 (unresolved, 1H), 5.74−5.78 (unresolved, 1H), 6.95−7.05 (unresolved, 2H), 7.45−7.55 (unresolved, 2H), 8.05−8.10 (unresolved, 1H), 8.18−8.22 (unresolved, 1H), 8.82−8.87 (unresolved, 1H), 11.49 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.96 (d, J = 13.5 Hz, 1H), 5.18 (d, J = 13.5 Hz, 1H), 5.83−5.87 (unresolved, 1H), 7.33−7.37 (unresolved, 2H), 8.98− 9.00 (unresolved, 1H), 11.24 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz) δ 47.4, 53.5, 55.4, 78.0, 114.4, 128.3, 128.7, 129.6, 130.2, 141.7, 145.0, 159.8; MS (ES+, Ar) m/z HRMS calcd for C14H15N4O3 ([M-Br]+) 287.1139; found, 287.1136.

7.10 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 10.22 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 48.2, 53.4, 78.8, 114.0, 114.9, 122.7, 126.7, 130.4, 131.6, 132.3, 139.9, 140.4, 143.2, 151.1; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 50.7, 52.9, 78.5, 114.2, 115.2, 122.4, 126.4, 129.9, 131.4, 132.6, 137.3, 139.6, 142.6, 151.9; 13C{1H} NMR (DMSO-d6, 125 MHz, tautomer) δ 37.9, 62.1, 77.9, 114.7, 115.7, 123.0, 125.6, 130.1, 132.0, 132.8, 138.4, 139.2, 142.9, 151.4; MS (ES+, Ar) m/z HRMS calcd for C14H13BrN3O2 ([M-Br]+) 334.0186; found, 334.0186. 8-Chloro-2-(4-methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7h). White solid; yield 117 mg, 97% (dr 88:12, inseparable); mp 208−210 °C; IR (KBr, cm−1) 3455 (br s), 2916 (m), 2873 (m), 2850 (m), 2819 (m), 2784 (m), 1653 (vs), 1593 (s), 1579 (s), 1551 (m), 1513 (m), 1252 (s), 1023 (m); 1H NMR (DMSO-d6, 400 MHz, major + minor) δ 3.77 (s, 3H), 4.48 (d, J = 14.5 Hz, 1H), 5.10 (d, J = 14.5 Hz, 1H), 5.54−5.58 (unresolved, 1H), 5.76−5.80 (unresolved, 1H), 7.01 (d, J = 7.1 Hz, 2H), 7.21 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.1 Hz, 2H), 7.45 (s, 1H), 8.27 (d, J = 5.5 Hz, 1H), 10.55 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.96 (d, J = 15.5 Hz, 1H), 5.19 (d, J = 15.5 Hz, 1H), 5.81−5.85 (unresolved, 1H), 10.31 (br s, 1H); 13C{1H} NMR (DMSO-d6, 100 MHz, major) δ 47.6, 53.3, 55.3, 78.5, 112.9, 114.1, 114.4, 128.5, 128.6, 141.0, 147.9, 150.7, 159.7; MS (ES+, Ar) m/z HRMS calcd for C15H15ClN3O3 ([M-Br]+) 320.0796; found, 320.0797. 7-Chloro-2-(4-methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7i). White solid; yield 110 mg, 92% (dr 74:26, inseparable); mp 205−206 °C; IR (KBr, cm−1) 3445 (br w), 3036 (m), 2978 (s), 2949 (s), 2900 (s), 2868 (s), 2817 (s), 1656 (m), 1567 (vs), 1514 (m), 1366 (m), 1252 (s), 1028 (m), 842 (m), 828 (m); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 3.77 (s, 3H), 4.46 (dd, J = 15.3, 2.8 Hz, 1H), 5.05 (d, J = 15.3 Hz, 1H), 5.54− 5.58 (unresolved, 1H), 5.74−5.78 (unresolved, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 7.6 Hz, 1H), 8.55 (s, 1H), 10.81 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.95 (d, J = 15.6 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 5.51−5.55 (unresolved, 1H), 5.79− 5.83 (unresolved, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 8.07−8.11 (unresolved, 1H), 8.53 (s, 1H), 10.48 (br s, 1H); 13 C{1H} NMR (DMSO-d6, 125 MHz, major) δ 47.8, 53.3, 55.3, 78.4, 114.4, 115.8, 118.4, 128.1, 128.4, 137.1, 142.6, 149.6, 159.7; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 50.5, 52.8, 55.2, 77.7, 114.2, 116.0, 118.5, 125.5, 128.8, 136.8, 142.1, 150.6, 159.9; MS (ES+, Ar) m/ z HRMS calcd for C15H15ClN3O3 ([M-Br]+) 320.0796; found, 320.0798. 7-Bromo-2-(4-methoxyphenyl)-3-nitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7j). White solid; yield 120 mg, 90% (dr 82:18, inseparable); mp 222−224 °C; IR (KBr, cm−1) 3432 (br m), 3077 (m), 3037 (m), 2969 (s), 2818 (m), 1652 (s), 1611 (m), 1593 (s), 1558 (s), 1513 (s), 1365 (s), 1254 (s), 1178 (m), 1166 (m), 1030 (m), 841 (m), 830 (m), 747 (m); 1H NMR (DMSO-d6, 500 MHz, major + minor) δ 3.77 (s, 3H), 4.47 (d, J = 14.8 Hz, 1H), 5.06 (d, J = 14.8 Hz, 1H), 5.53−5.57 (unresolved, 1H), 5.76−5.80 (unresolved, 1H), 7.00 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 8.13 (d, J = 9.1 Hz, 1H), 8.60 (s, 1H), 10.67 (br s, 1H); 1H NMR (DMSO-d6, 500 MHz, minor, peaks appearing separately) δ 4.98 (d, J = 15.7 Hz, 1H), 5.12 (d, J = 15.7 Hz, 1H), 5.80−5.84 (unresolved, 1H), 10.38 (br s, 1H); 13C{1H} NMR (DMSO-d6, 125 MHz, major) δ 47.7, 53.3, 55.3, 78.4, 105.0, 114.4, 115.8, 128.1, 128.4, 139.1, 144.8, 149.7, 159.7; 13C{1H} NMR (DMSO-d6, 125 MHz, minor) δ 50.4, 52.8, 55.3, 77.7, 104.9, 114.2, 116.0, 125.5, 128.7, 138.8, 144.2, 150.7, 159.9; MS (ES+, Ar) m/z HRMS calcd for C15H15BrN3O3 ([M-Br]+) 364.0291; found, 364.0290. 2-(4-Methoxyphenyl)-3,7-dinitro-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium Bromide (7k). Light yellow solid; yield 84 mg, 68% (dr 86:14, inseparable); mp 230−232 °C; IR (KBr, cm−1) 3432 (br m), 2874 (m), 2814 (m), 2785 (m), 1671 (vs), 1610 (s), 1585 (m), 1561 (s), 1535 (w), 1512 (m), 1348 (s), 1337 (s), 1284 (w), 1251 (m), 1182 (m), 1109 (w), 1027 (w), 839 (m); 1H NMR (DMSO-d6,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00947. X-ray file for compound 7b (CIF) 6486

DOI: 10.1021/acs.joc.7b00947 J. Org. Chem. 2017, 82, 6482−6488

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Copies of NMR spectra for all of the new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Irishi N. N. Namboothiri: 0000-0002-8945-3932 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS I.N.N.N. thanks SERB, DST India for financial assistance. L.S. thanks CSIR India for a senior research fellowship. We thank Ms. Deepa Nair, Department of Chemistry, IIT Bombay for help with X-ray data.

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